DESCRIPTION: There is no effective prophylactic HIV vaccine to prevent the 2.5 million new annual HIV infections. An ideal vaccine would elicit at least two kinds of immunity: antibody responses to reduce viral acquisition and CD8 T cell responses to control virus replication. There is ample evidence, from people with favorable host HLA genes, that particularly effective antiviral CD8 T cell responses maintain exceptional control of virus replication. Most of the population does not have these favorable HLA genes, so we need to devise ways to improve the efficacy of typically less potent host immune responses. There is also enormous diversity among circulating HIV sequences, but some functionally and/or structurally important regions of the genome do not appear to easily tolerate mutations. There is no evidence that CD8 T cell responses, in a host without protective HLA genes, can effectively target these less variable viral sequences. Establishing the value (or lack thereof) of conserved, or 'invariant,' epitopes in a vaccine is both timely and highly significant. Mauritian cynomolgus macaques (MCM) with identical major histocompatibility complex (MHC) class I genetics mount predictable and reproducible simian immunodeficiency virus (SIV) specific CD8 T cell responses. MCM infected with SIVmac239?nef maintain extremely low levels of viremia, and can be considered an MHC-independent model of HIV 'elite control.' We can manipulate the infecting viral sequence to 'knock out' the immunogenicity of different T cell epitopes, and thus break viral control. In this study, we will try to break elite control of SIVmac239?nef in animals with unfavorable genetics by 'knocking out' either the CD8 T cell responses targeting variable or invariant epitopes. We hypothesize that CD8 T cells that target conserved or 'invariant' epitopes do not efficiently detect and destroy virally- infected cells, evn when such CD8 T cells can produce antiviral cytokines in vitro. For the first time, the specificity and quality of these responses can be compared directly, with an aim towards understanding the best CD8 T cell responses to include in future vaccines. Our study makes use of an innovative system in which to directly test protective CD8 T cell responses. Although the PI of this project is a new investigator, she has studied SIV pathogenesis and SIV specific host immunity in MCM for six years. She made the important realization that this population of animals can be used to clearly define the value of CD8 T cell responses targeting these different categories of epitopes. By completing this project, she will further demonstrate the value of using MHC-identical MCM to study T cell immunity and T cell based vaccines and continue to pioneer this area of research.